Mice crucial in autoimmune research

A new Yale study on diabetes may enable breakthroughs in the prevention and treatment of autoimmune disorders.

Researchers at the Yale School of Medicine have discovered the mechanism behind teplizumab, an experimental drug used to treat Type 1 diabetes, an autoimmune disorder in which the body attacks its own insulin — producing cells in the pancreas. This study’s use of a mouse model may help develop treatments for other autoimmune diseases, including cancer, scientists interviewed said.

Teplizumab was developed in 2007 to stop the destruction of the insulin-producing cells by altering the function of certain T-cells, which regulate the immune system. Frank Waldron-Lynch, clinical fellow in Yale’s Department of Internal Medicine and lead author of the study, explained that while the results of teplizumab’s phase three clinical trial have been published already, the complete mechanism of teplizumab was unclear before now.

“The study is significant for understanding the nuance of treatment for Type 1 diabetes,” Waldron-Lynch said. “By understanding the mechanism of the drug, you gain an insight of how to better use that drug in patients.”

Waldron-Lynch’s team utilized the established humanized mouse model to study the mechanism behind teplizumab. The model, developed by researchers at the Jackson Laboratory, a non-profit biomedical research institution, enables scientists to study human immune systems without human subjects. Newborn immunodeficient mice are injected with human stem cells and develop human immune systems within 12 weeks.

The researchers found that in the mice, teplizumab caused specific T-cells to travel from the circulatory system to the small intestine. The T-cells then produced antibodies, which enabled them to regulate the immune system when the T-cells returned to the circulatory system. Previous studies had identified the T-cell antibodies as regulatory agents in the circulatory system, but the process occurring in the small intestine was unknown.

Kevan Herold, coresearcher and deputy director for translational science at the Medical School, said that while mice are different from people, the humanized mice model provides the best way for researchers to study drugs in mice and predict their effects on humans.

“If you have a mouse with a human immune system you can address a lot of questions [about the mechanism and effect of the drug],” Herold said.

In the same way that discovering the structure of penicillin enabled scientists to create more targeted drugs like amoxicillin, knowing more about the mechanism of teplizumab may lead researchers to develop more targeted therapies for type 1 diabetes, Waldron-Lynch added.

The study also opens doors to developments in the treatment of other autoimmune diseases, said Leonard Schultz, professor at the Jackson Lab. Improvements in the humanized mouse model could aid pharmaceutical companies in designing immunotherapy treatments for infectious and autoimmune diseases including cancer, inflammatory bowel disease and HIV.

The study was published on Jan. 25 in the journal Science Translational Medicine.